1. Field of the Invention
This invention is directed to a multiphasic estrogenic/progestogenic contraceptive regimen that may be used for an extended period of time. In the multiphasic regimen of the present invention, the amount of estrogen administered in each successive phase of the first three phases is greater than the amount of estrogen administered in the previous phase. The inventive regimen provides contraceptive efficacy and enables the user to maintain menstrual cycle control. A multiphase contraceptive kit that may be used to practice the method of this invention is also contemplated.
2. Related Background Art
Contraceptive compositions containing both estrogenic and progestogenic compounds are known to be highly effective in controlling ovulation and conception. The progestogenic component of the composition is primarily responsible for the contraceptive efficacy of the composition, while the estrogenic component is included to reduce undesired side effects, such as breakthrough bleeding or spotting. In fact, small amounts of estrogen help stabilize the endometrium and allow cyclic withdrawal bleeding, similar to the natural menstrual cycle.
The earliest of these estrogenic/progestogenic contraceptive compositions was administered monophasically (fixed dose) and contained a relatively high level of estrogenic component. To minimize estrogen's major negative side effect on blood clotting factors, the dose of estrogen was reduced over time. However, as estrogen doses decreased, the incidences of unwanted breakthrough bleeding or spotting have generally increased.
Multiphasic oral contraceptives were introduced to artificially simulate the natural rise of progesterone over the cycle in an attempt to solve this problem. A constant goal, however, has been to reduce the estrogenic potency of such compositions without reducing contraceptive efficacy and increasing undesired side effects.
In U.S. Pat. No. 5,888,543, various regimens are disclosed where a combination of progestin and estrogen are administered in a monophasic or multiphasic regimens (varied dose, e.g., biphasic or triphasic). In one embodiment, a combination of a progestin composition and an estrogen composition is administered such that the daily dosage of the second phase progestin is greater than the daily dosage of progestin in the first phase and the daily dosage of the second phase estrogen is greater than or equal to the daily dosage of estrogen in the first phase.
A particularly advantageous technique for reducing total estrogenic administration is described in U.S. Pat. No. 4,962,098. This describes a triphasic method of contraception using a progestogen/estrogen combination in which the amount of estrogen is increased stepwise over the three phases. The first phase is 4-7 days, the second phase is 5-8 days and the third phase is 7-12 days. Preferably, the administration of the contraceptive compositions for the three phases will be 21 days followed by a 7 day placebo period. For all three phases the progestogen is 0.5 to 1.5 mg of norethindrone acetate, while about 10 to 30 mcg of ethinyl estradiol is used in the first phase, about 20 to 40 mcg of ethinyl estradiol is used in the second phase and 30 to 50 mcg of ethinyl estradiol is employed in the third phase.
U.S. Pat. No. 5,010,070 is related to U.S. Pat. No. 4,962,098 and discloses a multiphasic contraceptive kit containing ethinyl estradiol and norethindrone acetate in first, second, and third phase compositions.
Recently, numerous oral contraceptive regimens extending treatment to three cycles have become known in the art. One such extended oral contraceptive regimen is disclosed in U.S. Pat. No. 5,898,032, where estrogen and progestin are administered in a combined dosage form, preferably monophasically, for 60 to 110 consecutive days, followed by an administration free period of 3 to 10 days. The amount of estrogen and progestin administered daily are equivalent to about 5-35 mcg of ethinyl estradiol and about 0.025 to 10 mg of norethindrone acetate, respectively. In one particular embodiment, the combined dosage form is administered for 84 days followed by 7 pill free days. Following this particular regimen is said to result in four treatments and menstrual cycles during the year.
Yet another extended oral contraceptive regimen is disclosed in U.S. Patent Application Publication No. 2005/0113350 A1, providing continuous hormonal treatment for a desired period of time longer than 21-28 days. Here, a first composition containing a progestin and estrogen is administered in the first 21-28 days, followed by a second composition of progestin and estrogen in an amount higher than the amount of the first composition, comprising a mono or multiphase sequence of dosages. The preferred regimen comprises dosages administered over an 84-112 day duration.
There are, however, disadvantages to using an extended monophasic oral contraceptive regimen. Typically, monophasic oral contraceptives administered for an extended period of time have poor initial cycle control.
Moreover, while perhaps reducing the number of periods to four per year, another drawback of conventional monophasic oral contraceptive regimens extended over three cycles is the excessive breakthrough bleeding that often results. Breakthrough bleeding, or spotting, is the undesired bleeding that sometimes occurs between regular withdrawal bleeding periods. It is believed that breakthrough bleeding is increasingly difficult to effectively suppress as durations of treatment extend beyond one month. With many three-cycle regimens, irregular bleeding occurs with increasing frequency as the treatment begins to break down until the oral contraceptive is withdrawn at the end of third cycle, finally resulting in the onset of the expected withdrawal bleeding. While excessive breakthrough bleeding may be diminished by using a higher dose of estrogen, this solution inevitably brings with it the risk of negative side effects of elevated estrogen on blood clotting factors. Finally, once breakthrough bleeding is under control, the user becomes functionally amenorrheic. Psychologically, this does not reassure the user that she is not pregnant.
Accordingly, there is presently a need for an extended oral contraceptive regimen that significantly reduces the occurrence of breakthrough bleeding commonly associated with three-month extended cycle regimens while at the same time only gradually increasing the dosage of estrogen delivered over the course of treatment.